We have documented that activation of GABA receptors in the hindbrain of the cat causes respiratory arrest and that blockade of these receptors causes respiratory stimulation. The objective of our proposed research will be to determine the specific location of these GABA receptors and/or GABAergic synapses in the CNS and to evaluate the role of CNS GABAergic mechanisms in the control of breathing. This will be done by: 1) applying GABA and drugs that stimulate GABA receptors in specific hindbrain areas known to comprise part of the CNS respiratory apparatus; 2) applying drugs which either selectively block GABA receptors or inhibit the synthesis of GABA in the specific neural sites defined in (1) and observing whether a selective enhancement in respiratory activity occurs; 3) applying drugs which selectively increase endogenous GABA levels in the specific neural sites defined in (1) and observing whether a selective depression of respiratory activity occurs; 4) pretreating animals with drugs that either enhance or block CNS GABAergic mechanisms and observing whether these manipulations will modify respiratory responses evoked by afferent input from the lungs, carotid and aortic body chemoreceptors, skeletal muscle; elevated concentrations of alveolar CO2; and respiratory depressant drugs such as the barbiturates and the benzodiazepines. Anatomical connections between the hindbrain site of action of GABAergic drugs and the phrenic motor nucleus will also be sought. Methods to be used include measuring tidal volume, minute volume, respiratory rate, tracheal occlusion pressure, esophageal pressure, dynamic lung compliance, end tidal CO2, and blood gases. Calculations of inspiratory, expiratory and total cycle durations will be made from rapid tracings. Phrenic nerve activity will also be measured in some animals. The technique of retrograde axonal transport of horseradish peroxidase will be used to determine anatomical connections. The results obtained from these studies should define: 1) site(s) in the brain where GABA abolishes respiratory activity; and 2) the role of endogenous GABA in regulating this vital function. The results obtained may also aid in our understanding of the CNS depressant actions of the barbiturates and benzodiazepines and may point out a potential factor (i.e. accumulation of GABA in the CNS) that could contribute to the Sudden Infant Death Syndrome and to Adult Apneic Syndromes.